Catalytic Asymmetric Chlorination & Bromination

Strategies for Catalytic Asymmetric Electrophilic
a Halogenation of Carbonyl Compounds
R 1
R 2
O
Y
Catalyst
[X + ]
Hintermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 – 4362
Hamashima, Y.; Sodeoka, M. et al J. Am. Chem. Soc. 2002, 124, 14530 –14531
France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 – 4255
Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 – 4109
Halland, N. ; Jørgensen, K. A. et al J. Am.Chem. Soc. 2004, 126, 4790 – 4791
Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 – 5510
Zhang, Y. ; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038 –15039
Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 – 5 (early view)
Ali Z. Ding
Advisor: Prof. W. D. Wulff
May 12 2005
R 1
X
!
R 2
O
Y

Introduction
a-Halogenated Carbonyl Compounds
Linchpins for further stereospecific manipulations
Halogen substituents can sometimes dramatically alter its physical, chemical
and biological properties
Increasingly important structural motifs in medicinal chemistry and material
sciences.
F 3C
MeO
F
Currently being assessed worldwide in phase III clinical trials
for treatment of acute ischemic stoke
Oestreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147 – 1155
N
H
O
BMS-204352
MaxiPost
Cl

Introduction
Approaches to the Chiral a-Halogenated Carbonyl Compounds
(1) Reagent-controlled halogenation: asymmetric halogenation of enolates using chiral
electrophilic halogenating agents
R 1
(2) Substrate-controlled halogenation: diastereoselective electrophilic halogenation of
chiral enolates or enol ethers
R 1
(3) Catalytic asymmetric halogenation of carbonyl compounds
R 1
R 2
R 2
O
R 2
O
O
Y
Y*
Y
!
R
[X + ]
[X + ]
Catalyst
[X + ]
Oestreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327
Taylor, S. D.; Kotoris, C. C. and Hum, G. Tetrahedron, 1999, 55,12431-12477
R 1
R 1
R 1
X
X
!
R 2
!
R 2
X
O
!
R 2
O
O
Y
Y*
Y

Noncatalytic Halogenation
Substrate-controlled Halogenation: Use of Chiral Auxiliaries
Oestreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327
Taylor, S. D.; Kotoris, C. C. and Hum, G. Tetrahedron, 1999, 55,12431-12477

Noncatalytic Halogenation
Reagent-controlled Halogenation: Chiral Fluorinating Reagents
Pioneering work: Differding, E. and Lang, R. W. Tetrahehron Lett. 1988, 29, 6087-6090
• Moderate yields and low to moderate enantioselectivities
• Syntheses of these reagents require several steps
Wong, C.-H., Angew. Chem. Int. Ed., 2005, 44, 192
Taylor, S. D.; Kotoris, C. C. and Hum, G. Tetrahedron, 1999, 55,12431-12477

Noncatalytic Halogenation
Reagent-controlled Halogenation: Cinchona Alkaloids Fluorinating Reagents
N
OH
[F + ]
N
F
X -
OH
[F + ] =
Cl
PhSO2 N
2BF - N F
4
N
F
PhSO2 N
N
Selectfluor,
or F-TEDA
N-fluorobenzenesulfonimide
or NFSI
10 11 12 13
Cinchona alkaloids (CA) are readily available in both pseudo-enantiomeric forms
Easily prepare, more reactive
Can be generated and used in situ
Can be “reloaded” by F-TEDA or NFSI and reused without loss in selectivity
Can such CA be used catalytically in these reactions?
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147 – 1155

Catalytic Asymmetric Fluorination
Organo-Catalytic Enantioselective Fluorination by Phase-Transfer Catalysts
Kim, D. Y. and Park, E. J. Org. Lett., 2002, 4, 545–547.

Catalytic Asymmetric Fluorination
Organo-Catalytic Enantioselective Fluorination by L-Proline Derevatives
R
O
Challenges:
H
+ F + Source
• N-fluorination of catatlyst
• Fluorination of substrate should be faster
• Racemization and difluorination
• Both SM and product can form enamine species
• a-proton of product is more acidic
• F atom is not big enough to contribute to an added steric shielding
• Products are not stable to survive silica gel
N
H
F !
• Screen catalysts and solvents
• Lower the catalyst loading
• Screen fluorinating reagents
Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 – 5
R*
R
O
H
NaBH 4 F !
R
OH

Catalytic Asymmetric Fluorination
Organo-Catalytic Enantioselective Fluorination by L-Proline Derevatives
O
N
H X
14a, X= OH
14b, X= NH2 R
O
H
Ph
N
H
Ph
15 16,
NFSI, 16(1mol%)
MTBE, RT
• In the solvents other than MTBE, catalyst 16 decomposes
• Products were reduced to alcohol in situ
Dr. MacMillan’s Work:
OTMS
N Ar
H Ar
Enantioselective Organocatalytic Direct a-Fluorination:
F
R
Beeson, T. D. and MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, in press
True nucleophiles toward electrophilic fluorine: enols, enolates or enamines
CF 3
CF 3
Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 – 5
O
H
Ar=
NaBH 4
MeOH, RT
R= Pr (96%ee), Bu(91%ee), Hex (96%ee), BnO(CH 2) 3(91%ee),
Bn (93%ee), Cy (96%ee), tBu(97%ee), 1-Ad (96%ee)
F
!
R
OH
MTBE=
Yield: 55-95%
O
PhSO2 N
PhSO2 NFSI
F

Catalytic Asymmetric Fluorination
Chiral Lewis Acid Catalyzed Asymmetric Fluorination
• Addition of sub-stoichiometric amount of Lewis acid significantly
accelerates formation of fluorination product
12 17 18
Ti-based Lewis acids are the most potent catalysts
Umemoto, T et al J. Am. Chem. Soc., 1990, 112, 8563–8575
Hintermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 – 4362

Catalytic Asymmetric Fluorination
TiCl 2 [R,R-(TADDOLLato)] Catalyzed Asymmetric Fluorination
12
Hintermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 – 4362
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147 – 1155

Catalytic Asymmetric Fluorination
Mechanism of Ti Catalyzed Asymmetric Fluorination
Piana, S.; Togni, A. et al Angew. Chem., Int. Ed., 2002, 41, 979–982
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147 – 1155
12
The bidentate nature of substrates is beneficial for high facial selectivity

Catalytic Asymmetric Fluorination
Asymmetric Fluorination Catalyzed by Other Lewis Acids
13
Alcoholic solvents can work well
Not sensitive to water
Catalyst can be recycled and re-used without loss of any slectivity
Hamashima, Y.; Sodeoka, M. et al J. Am. Chem. Soc., 2002, 124, 14530–14531.

Catalytic Asymmetric Fluorination
O
N N
Ph
M
Ph
Asymmetric Fluorination Catalyzed by Other Lewis Acids
O
62 M= Cu, X - = OTf
63 M= Ni, X - = ClO 4
X -
13
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147 – 1155
Ma, J.-A. and Cahard, D. Tetrahedron: Asymmetry, 2004, 15, 1007
HFIP=
F 3C CF 3
Shibata, N.; Ishimaru, T.; Nagai, T., Kohno, J. and T. Toru Synlett 2004, 1703 –1706
OH

Catalytic Asymmetric Chlorination & Bromination
R 1
O O
Me
Chiral Lewis Acid Catalyzed Asymmetric Chlorination & Bromination
OR 2
Me OBn
Me
R 1
O O
O
+ N
O
Cl
+
I Cl
64 65
O O
R 2
R 3
O
+ N
O
X
X
5mol%
38 or 39
MeCN, rt
5mol% 38
1.2eq py
toluene, 50 o C
10mol% 67
R 1
O O
X Me
O O
OR 2
Hintermann, L. and Togni, A. Helv, Chim. Acta, 2000, 83, 2425–2435
X= Cl, up to 88%ee
X= Br, up to 23%ee
Me OBn
Cl Me
(S)-66, 67%, 71%ee
With Cl2, (S)-66, 62%, 30%ee
Hintermann, L. and Togni, A. Helv, Chim. Acta, 2004, 87, 605–610
Et 2O
R 1
O O
R 2 X
OR 2
X= Cl, up to 77%ee
X= Br, up to 82%ee
Marigo, M.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Eur. J. 2004,10, 2133 – 2137
Oestreich, M. Angew. Chem. Int. Ed., 2005, 44, 2324-2327
O
O
N N
t-Bu
Cu
(S, S)-67
t-Bu
2 OTf -

Catalytic Asymmetric Chlorination & Bromination
Cl
O
67
R
Organo-Catalyzed Asymmetric Chlorination & Bromination Acyl Halides
Tadem halogenation/esterification process of acyl halides
Cl
Cl
MeO
Cl
Cl
Base
THF
-78oC Cl
Cl
O
N
69
N
O
Br
Br
C
R
68 (2.0eq)
O Ph
O
Br
70 71
Br
O
69(10mol%)
70 or 71 (1.0eq)
THF, -78 o C
Nu
LG X
ArO
O
R
X 72
+ Nu
O
74
LG -
X
LG
R
O
LG -
X
R
72
Nu
69
LG X
+ Nu
70 or 71
The choice of chlorinating agents is pivotal for the reaction to turn over
France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 – 4255
O
O -
C
68
R
R
73
Base
Cl
O
67
R

Organo-Catalytic Asymmetric Chlorination & Bromination
Optimization of Reaction Conditions
The choice of chlorinating agents: the window is very narrow
The choice of base: reactive, cheap, easy to handle
Me 2N NMe 2
R
O
X
N O
O Cl
Unreactive: Too reactive: ,
Me 2N NMe 2
67 68
70
C6Cl5O H
Me2N NMe2 69
70 71
O
C
R
75
76
Cl 5C 6O
France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 – 4255
Cl 2
O
R

Organo-Catalytic Asymmetric Chlorination & Bromination
Choice of Base and Summary
O
Cl
67
R
NaH, 15-crown-5
69(10mol%), 70(1.0eq)
THF, -78oC to rt, 4h
O
R
Cl5C6O Cl
75
R= Ph, PhOCH2, 1-Np, p-NO2Ph, Et, o-ClPh Yield: 43-79%, ee: 90-99%
Cl
O
67
R
NaHCO3, 15-crown-5
69(10mol%), 70(1.0eq)
ClPh, -35oC to rt, 5h
R= Ph, PhOCH2, 1-Np, p-MeOPh
Moderate yields, high enantioselectivity
Inexpensive reagents
Can be scaled up
O
R
Cl5C6O Cl
75
Yield: 56-68%, ee: 88-91%
Ketenes from other sources (Wolff rearrangement) can be used as well
France, S.; Lectka, T. et al J. Am. Chem. Soc. 2004, 126, 4245 – 4255

Organo-Catalytic Asymmetric Chlorination
Asymmetric Chlorination of Aldehydes Catalyzed by Chiral Amines
76 77
78
70
8 examples
Yield: 60-88%
ee: 97-99%
Such cyclic transition state might enforce activation of 70 in the asymmetric environment
of an e-rich enamine mediated by proton
Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 – 4109
70
79
80

Organo-Catalytic Asymmetric Chlorination of Aldehydes
Asymmetric Chlorination of Aldehydes: Catalysts and Chlorinating Reagents
82
83
82
83
70
70
70
70
81 82 83
L-Proline doesn’t work well
NCS doesn’t work well
Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 – 4109
Cl
Cl
Cl
N
O O
NCS
Cl
Cl
70
Cl
Cl
O

Organo-Catalytic Asymmetric Chlorination of Aldehydes
Asymmetric Chlorination of Aldehydes: the Solvent Effects
Inert to halogenation reagent
Optimal selectivity, reaction rate, and chemical yield
82
Product epimerization, formation of R,R-dichlorooctanal, or octanal aldol
dimerization were comprehensively suppressed using these conditions
Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 – 4109
82

Organo-Catalytic Asymmetric Chlorination of Aldehydes
Asymmetric Chlorination of Aldehydes: The Scope
Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 – 4109

Organo-Catalytic Asymmetric Chlorination of Aldehydes
70
Asymmetric Chlorination of Aldehydes: b-Chiral Aldehydes
Internal asymmetric induction is almost completely over-compensated
Selectivity is sterically and chemically good
Substrate scope is broad
All the reagents (70, 82 and - 82) are bench stable and commercially available
Products are stable
- 82
82
Brochu, M. P.; Brown, S. P. ; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108 – 4109

Organo-Catalytic Asymmetric Chlorination of Aldehydes
Asymmetric Chlorination of Aldehydes: Jørgensen’s Work
H
O
iPr
Catalyst
NCS
Halland, N. ; Jørgensen, K. A. et al J. Am.Chem. Soc. 2004, 126, 4790 – 4791
H
O
!
Cl
iPr
Ph
Cl
N
O O
NCS
O
N
H NH2 3c
N
H
3i
Ph

Organo-Catalytic Asymmetric Chlorination of Aldehydes
Asymmetric Chlorination of Aldehydes: The Scope
H
O
NCS (1.3eq) O
1
R
3c or 3i (10mol%)
CH2Cl2, rt, 1-10h
H
! R
Cl
2
Asymmetric Bromination & Iodination of Aldehydes
H
H
O
O
1d
1a
NBS
3i (10mol%)
CH 2Cl 2, rt
NIS
3i (10mol%)
CH 2Cl 2, rt
Halland, N. ; Jørgensen, K. A. et al J. Am.Chem. Soc. 2004, 126, 4790 – 4791
H
H
O
O
!
I
!
Br
80%ee
24%ee
Ph
Cl
N
O O
NCS
O
N
H NH2 3c
N
H
3i
Ph

Organo-Catalytic Asymmetric Chlorination of Ketones
Organo-Catalyzed Asymmetric Chlorination of Ketones
Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 – 5510
Cl
N
O O
NCS

Organo-Catalytic Asymmetric Chlorination of Ketones
Asymmetric Chlorination of Ketones: Effects of Additives & Solvent
CH 3 CN is the best solvent
Significant improvement by adding acids:
• Promotion of enamine formation
• Suppression of catalyst chlorination
Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 – 5510
Ph
Ph
Cl
N
O O
NCS
H
N
N
H
3i

Organo-Catalytic Asymmetric Chlorination of Ketones
R
O
1
R
Asymmetric Chlorination of Ketones: The Scope
3i (20mol%)
2-NO 2-PhCO 2H (50mol%)
NCS (2eq), MeCN, 20h
R
O
2
!
Cl
R
Ph
Ph
High e.e.
H
N
N
H
3i
Moderate yields: poly-chlorination occurs
Broad substrate scope
Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2004, 43, 5507 – 5510
Cl
N
O O
NCS

Asymmetric Chlorination of Ketones
Back to Reagent Controlled Asymmetric Chlorination of Ketones
Reagent-controlled process can sometimes be competitive alternative!
R 1
OSi
R 2
R 3
+
X
O
X
Cl Cl 1
Zhang, Y. ; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038 –15039
O
Lewis acid
X=R or OR R 1
O
!
R 3
Cl R 2
Chirality of auxiliary (X) could be transferred to silicon enolates
Lewis acids are necessary to activate 1
Chlorinating reagents 1 can be prepared easily

Asymmetric Chlorination of Ketones
Asymmetric Chlorination of Ketones: Effects of X group & Si Group
ZrCl 4 is uniquely reactive
The size of X group
The size of si group
Yields are high (>90%)
Zhang, Y. ; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038 –15039

Asymmetric Chlorination of Ketones
Asymmetric Chlorination of Ketones: Scope

Asymmetric Chlorination of Ketones
Asymmetric Chlorination of Ketones: Potential to be Catalytic
O
O
OSi
( ) n
O O
1-Np Cl Cl 1-Np
1c
CF 3SO 2H
ZrCl 4
O
( ) n
O
Cl
O
O O
1-Np H Cl
2c
1-Np
CF 3SO 2Cl
2c can be easily recovered and chlorinated back to 1c
Recovered 1c can be re-used for the reaction
This novel process might be extended to catalytic asymmetric variants!
Zhang, Y. ; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038 –15039

Catalytic Asymmetric Halogenation of Carbonyl Compounds
Conclusions
• Enantioselective electrophilic a-halogenation of carbonyl compounds: a topical
area of current asymmetric catalysis
• A new tool has presented itself to synthetic organic chemistry
• More applications are expected

Dr. Togni
ETH
Dr. MacMillan
Caltech
Cl
Cl
Cl
N
N
F
O
PhSO 2
2BF -
4 N F
PhSO 2
Selectfluor,
or F-TEDA N-fluorobenzenesulfonimide
or NFSI
12 13
Cl
Cl
Cl
Br
Br
Br
O
X
N O
Cl
To What They Should Thank?
Br
70 71
Wong, C.-H., Angew. Chem. Int. Ed., 2005, 44, 192
O
Dr. Jørgensen
Aarhus U.
X= Cl, NCS
X= Br, NBS
X= I , NIS
Taylor, S. D.; Kotoris, C. C. and Hum, G. Tetrahedron, 1999, 55,12431-12477
Dr. Lectka
Johns Hopkins U.
Dr. Yamamoto
U. of Chicago